We propose to study the role of cyclic nucleotides in the regulation of interstitial pulmonary inflammation. In previous studies, we have shown that interstitial inflammation, as induced in the rabbit by inhaled antigen/mitogen mixtures, can be prevented by systemic administration of cholera toxin, in association with elevation in peripheral blood lymphocyte cAMP, and decreased responsiveness of these cells to mitogen stimulation in vitro. We now propose to characterize the relationships between cAMP content, cell activation and susceptibility to antigen/mitogen-induced disease, using alveolar macrophages and lymphocytes isolated from the lung. In addition to more clearly defining the action of CT in preventing aerosol-induced interstitial pneumonitis, we will also determine whether individual susceptibility to environmental lung disease in general can be predicted on the basis of indigenous levels of lymphocyte cAMP and/or lymphocyte responsiveness to mitogen-induced polyclonal cell activation. We also plan to modify pulmonary inflammation selectively; that is, we will prevent antigen/mitogen-induced interstitial inflammation by local (aerosol) administration of cAMP agonists, while preserving the competence of inflammatory mechanism elsewhere in the host. Alternatively, in separate experiments, we shall "rescue" the lung of a systemically immunosuppressed host by local administration of cGMP agonists.